Cannabis: alteraciones cognitivas y Psicosis

Presentación del tema: "Cannabis: alteraciones cognitivas y Psicosis"— Transcripción de la presentación:

1 Cannabis: alteraciones cognitivas y Psicosis
Gabriel Handlarz 6L 3I

2 From the President April 18, 2014
Marijuana Legalization and Young Brains: Time for Serious Study Robert Dupont, M.D.; Jeffrey Lieberman, M.D.

3 Robert Dupont, M.D.; Jeffrey Lieberman, M.D.
While we debate and differ on the risks and benefits of legalization, decriminalization, and medical uses of marijuana, all will agree (or say they do) that marijuana should remain illegal for young people. However, we should not deceive ourselves; just like with alcohol and tobacco, young people will almost certainly have ready access to pot with the liberalization of our laws and the commercialization of marijuana. What we are missing in fully understanding the ramifications of this new legislation, which can have broad effects on our country and culture, is firsthand knowledge of how marijuana affects the brain, particularly the young brain. Without more scientific evidence, we are gambling with the health and safety of our young people based on speculation and wishful thinking.

4 Over 106 million Americans have tried it at ….least once
Marijuana is the Most Commonly Used Illicit Drug In the U.S. Over 106 million Americans have tried it at ….least once An estimated 2.4 million Americans used it for .the first time in 2010 Marijuana is the most commonly abused illicit drug in this Country. Delta-9-tetrahydrocannabinol (THC) is the main active ingredient in marijuana, responsible for many of its known effects. Source of Statistics: Substance Abuse and Mental Health Service Adminstration (SAMHSA) National Survey on Drug Use and Health Tetrahydrocannabinol (THC) Active Ingredient in Marijuana Source: National Survey on Drug Use and Health, SAMHSA, 2010.

5 Why Do People Take Drugs in The First Place
Why Do People Take Drugs in The First Place? They like what it does to their brains The question is often asked: Why would anyone abuse drugs? Research has shown that people generally take drugs to either feel good (i.e., sensation seekers, or anyone wanting to experiment with feeling high or feeling different) or to feel better (i.e., self-medicators, or individuals who take drugs in an attempt to cope with difficult problems or situations, including stress, trauma, and/or to lessen anxiety, fears, depression, or hopelessness). To Feel Good To Feel Better Image courtesy: Vivian Felsen

6 Most people who use cannabis don’t develop problems

7 Cannabis –Cognición_ Psicosis
Potencia Frecuencia Edad de Inicio Vulnerabilidad

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14 The ingredients of cannabis
Tetrahydrocannabinol (THC) – partial agonist at CB1 High doses cause impairment of attention, memory and learning, hallucinations and paranoid ideas Cannabidiol (CBD) – inverse agonist at CB1 Is not hallucinogenic Has anxiety relieving properties Antagonises effects of THC Antipsicotico? THC CBD

15 The ingredients of cannabis
THC causes Impairment of attention, memory and learning Hallucinations and paranoid ideas Cannabidiol (CBD) Is not hallucinogenic Has anxiety relieving properties Antagonises effects of THC THC CBD

16 Cannabis potency in England
Skunk THC content (%) 2 4 6 8 10 12 14 1995 1996 1997 1998 1999 2000 2001 2002 2004 Imported Herbal Resin 2008 Potter et al 2008, DoH, 2008

17 AS THC has increased, has CBD decreased?
Is Cannabis getting stronger? Concentration of THC in traditional cannabis, 1-4% By 2003 in the US this had risen to 7%. In Europe the average THC concentration in sinsemilla doubled to 12% In some forms in the Netherlands 20% AS THC has increased, has CBD decreased?

18 Is Cannabis getting stronger?
Potency of D9–THC and Other Cannabinoids in Cannabis in England in 2005: Implications for Psychoactivity and Pharmacology* Sinsemilla was the most common form found overall, accounting for 55% of the samples seized. Potter D.J. et al (2008) J Forensic Sci.53:1

19 Cannabis alteraciones cognitivas y Psicosis
Edad de Inicio

20 SOURCE: University of Michigan, 2011 Monitoring the Future Study
In 2009, Reports of Past Month Use of Marijuana Among 12th Graders Exceeded that of Cigarette for the First Time in the Survey’s History Past month marijuana use in teens exceeds that of tobacco use. The data shown are for 12th graders, but the same pattern is seen for 8th and 10th graders, according to NIDA’s Monitoring the Future (MTF) Survey. These trends show that although we have been making progress in deterring young people from using tobacco products, we have to redouble our efforts to erode the perception that marijuana is a benign drug. For more information on MTF, see: SOURCE: University of Michigan, 2011 Monitoring the Future Study

21 El consumo de marihuana daña la inteligencia, señala un estudio (Clarín 28 de agosto 2012)
Se trata de un relevamiento de más de mil personas durante 20 años en Nueva Zelanda; el perjuicio es mayor en los jóvenes; el informe es de investigadores del Reino Unido y EE.UU                                                                                  Un joven arma un cigarrillo de marihuana en una marcha en Buenos Aires. Foto: EFE  (EFE).- La marihuana puede causar daños duraderos en la inteligencia y afectar la atención y la memoria de una persona si comienza a consumirse antes de los 18 años, según un nuevo estudio publicado en la revista "Proceedings of the National Academy of Sciences" (PNAS). Los adolescentes que consumen marihuana de manera habitual antes de los 18 años pueden tener daños duraderos en la inteligencia y afectar a la atención y a la memoria según un estudio publicado en "Proceedings of the National Academy of Sciences" (PNAS). El estudio, realizado por un equipo internacional de científicos entre más de jóvenes neozelandeses, detectó que aquellos que comenzaron a fumar marihuana en la adolescencia y continuaron consumiéndola tuvieron una disminución en su coeficiente intelectual. En concreto la reducción fue de 8 puntos, al comparar el coeficiente intelectual de los participantes en el estudio a los 13 años y a los 38 años y según Madeline Meier, de la Universidad de Duke e investigadora principal, dejarlo no parece que revierta los efectos. La clave está en la edad a la que se empieza a consumir en relación a la etapa de desarrollo del cerebro, explica Meier, ya que los que no consumieron marihuana hasta la edad adulta, cuando ya está formado por completo el cerebro, no mostraron este descenso en sus facultades. La experta explica que antes de los 18 años el cerebro se está desarrollando todavía y puede ser mas vulnerable a los daños que provocan las drogas, por lo que la marihuana, en este caso, también tiene un efecto en los jóvenes.

22 Entrevistas a los 18, 21, 26, 32 y 38 años.
Persistent cannabis users show neuropsychological decline from childhood to midlife (Meier et al PNAS 2012) Estudio Dunedin (The Dunedin Multidisciplinary Health and Development Research Unit -New Zealand ) 1037 individuos seguidos desde el nacimiento 1972/73 hasta los 38 años. Entrevistas a los 18, 21, 26, 32 y 38 años. Test neuropsicológicos a los 13 y 38 años luego del patrón de consumo.(1985/6-2010/12)

23 >función ejecutiva >velocidad de procesamiento
Se investigo la asociación del persistente consumo de cannabis y el funcionamiento neuropsicológico Se investigo el efecto del cannabis en 5 diferentes áreas de funcionamiento mental a los 38 años: >función ejecutiva >velocidad de procesamiento <Memoria de trabajo <Razonamiento perceptual <Comprensión verbal

24 La mayor dependencia al cannabis muestran mayor deterioro del IQ.
Se investigo la asociación del persistente consumo de cannabis y el funcionamiento neuropsicológico El cambio de IQ de la adolescencia a la adultez es función del uso persistente de cannabis. La mayor dependencia al cannabis muestran mayor deterioro del IQ.

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26 El uso en la adolescencia es determinante para la caída del IQ.

27 Correlations between cannabis use and IQ change in
the Dunedin cohort are consistent with confounding from socioeconomic status Ole Rogeberg The Ragnar Frisch Centre for Economic Research, N-0349 Oslo, Norway Edited by Leslie Lars Iversen, University of Oxford, Oxford, United Kingdom, and approved December 7, 2012 (received for review September 8, 2012)

28 Who Are the Adolescent-Onset Cannabis Users?
Correlations between cannabis use and IQ change in the Dunedin cohort are consistent with confounding from socioeconomic status Ole Rogeberg1 Who Are the Adolescent-Onset Cannabis Users? Although Meier et al. do not present a table of background variables and average scores by cannabis-use groups, the extensive publications on the Dunedin cohort indicate that early-onset cannabis use is more common for those with poor self-control, prior conduct problems, and high scores on risk factors correlated with a low family SES . Based on results from a similar cohort, a likely consequence of this is that Maori participants will be overrepresented .

29 What Are Counterfactual IQ-Trajectories for Those at Risk for High Cannabis Exposure?
The first assumption is that noncognitive factors related to SES influence the future environment of an individual (education, occupation, and so forth). At a general level, this is known to be the case in that SES predicts educational attainment after controlling for individual IQ . Although IQ gains from early intervention programs tend to fade in the years following an intervention , the programs can nevertheless show large effects on long-term educational and occupational outcomes . These effects consequently work through noncognitive factors, “hypothesized to be related to differences in motivation, perseverance, temperament, and other dimensions of social competence” .

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32 Why do only some cannabis users go psychotic?
As we have seen, the study of GxE is in its very early stages. I outlined steps we have adopted to conduct this research. Important to step back and ask, why is it useful to do GxE studies? What are the promises of this research? First, Implications for neuroscience. Psychosis Vulnerability

33 Does cannabis increase the risk of chronic psychotic illness?
Country N Follow up OR (95% CI) Study Design Reference USA 4,494 NA 2.4 Population based Tien et al, 1990 Sweden 50,053 25 yrs 2.1 Conscript Cohort Andreasson et al, 1987 Zammit et al, 2002 Netherlands 4,045 3 yrs 2.8 Van Os et al, 2002 Israel 9,724 4-15 yrs 2.0 Population based Weiser et al, 2002 New Zealand (Christchurch) 1,265 1.8 Birth-cohort Fergusson et al, 2003 (Dunedin) 1,253 15 yrs 3.1 Arsenault et al, 2002 1,580 14 yrs Ferdinand et al 2005 Germany 2,436 4 yrs 1.7 Henquet et al, 2005 United Kingdom 8,580 18 months 1.5 Wiles et al, 2006 Murray et al Nature Reviews Neuroscience 8:

34 Vulnerabilidad genética y psicosis
Una vulnerabilidad genética puede favorecer la inducción de esquizofrenia por el consumo de cannabis. Así se ha observado la asociación entre un polimorfismo genético de la Catecol-O-Metil Transferasa (COMT) con la inducción de psicosis por el cannabis. Los pacientes que tenían menor actividad dopaminérgica por la presencia de una enzima COMT menos activa y presentaban un consumo de cannabis más precoz serían los de mayor riesgo (Caspi, Moffitt, Cannon, McClay, Murray y Harrington, et al., 2005).

35 Caspi et al, Biological Psychiatry, 2005
Are some people more vulnerable to cannabis-psychosis? The influence of early-onset cannabis use on adult psychosis is moderated by COMT genotype 151 48 311 91 148 54 No adolescent cannabis use Adolescent cannabis use Caspi et al, Biological Psychiatry, 2005

36 rs G-A-C alleles

37 B rs G-A-C alleles The protein encoded by the gene AKT1 is a serine/threonine kinase, whose main function is the phosphorylation and consequent inactivation of glycogen synthase kinase (GSK-3). Cannabinoids are able to activate the AKT1/GSK3 pathway by acting on CB1 and CB2 receptors in vitro(Sanchez et al, 2003) and acute administration of THC in mice also activated AKT1 in vivo (through AKT1 phosphorylation) in several brain areas, including the striatum, independent of dopamine D1 and D2 receptor blockade (Ozaita et al, 2007).

38 rs G-A-C alleles

39 rs G-A-C alleles

40 rs G-A-C alleles Figure 1 Continuous Performance Test (CPT) performance as a function of cannabis use and AKT1 rs genotype. (a) CPT–mean reaction time (in ms). (b) CPT–accuracy (% correct).

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48 Genetic predisposition to schizophrenia associated with
Molecular Psychiatry (2014), 1–4 © 2014 Macmillan Publishers Limited All rights reserved /14 ORIGINAL ARTICLE Genetic predisposition to schizophrenia associated with increased use of cannabis RA Power1,2, KJH Verweij3, M Zuhair1, GW Montgomery4, AK Henders4, AC Heath5, PAF Madden5, SE Medland4, NR Wray

49 Cannabis como componente en la causa de Psicosis
Es porque el cannabis aumenta directamente el riesgo de psicosis O Los mismos genes que incrementan el riesgo de psicosis aumentan el riesgo de uso de cannabis

50 ESTUDIO CON EAGC DE MAS DE 13000 EZQUIZOFRENICOS Y MAS DE 18OOO SANOS
Genetic predisposition to schizophrenia associated with increased use of cannabis Molecular Psychiatry (2014), 1–4 RA Power1 , KJH Verweij3, M Zuhair SE TESTEO EL SCORE DE RIESGO POLIGENICO PARA EZQUIZOFRENIA Y EL USO DE CANNABIS EN 2081 INDIVIDUOS SANOS. (INDIVIDUOS CON ALELOS CON CARGA AUMENTADA PARA EZQUIZOFRENIA-SCHIZOPHRENIA POLYGENIC RISK SCORES ) ESTUDIO CON EAGC DE MAS DE EZQUIZOFRENICOS Y MAS DE 18OOO SANOS

51 Estudios de asociación del genoma completo: lo que necesita saber un psiquiatra* Nick Craddock
El término “estudios de asociación del genoma completo” (EAGC) refiere a un novedoso abordaje de investigación genética molecular a gran escala que ha generado, en los últimos cinco años, contribuciones mayores para el avance de nuestro entendimiento de muchas enfermedades humanas comunes, incluyendo la diabetes, cardiopatías, enfermedad inflamatoria intestinal, varios cánceres y artritis reumatoidea. Los estudios están comenzando a proveer discernimientos sobre la etiología y patogénesis de enfermedades psiquiátricas mayores, incluyendo las relaciones biológicas entre las categorías diagnósticas tradicionales

52 EAGC Las distintas formas de una variante dada en la secuencia de ADN son llamadas alelos. Hay muchas clases de variación genética. Partiendo de cuán común es una variante dentro de la población, algunas variantes son muy raras (son usualmente llamadas mutaciones) y otras son comunes (generalmente llamadas polimorfismos) Una variante común de un solo par de bases se llama polimorfismo de nucleótido simple (PNS); ésta es la variante principal que se busca en los EAGC.

53 EAGC En este tipo de estudio se examina un número muy grande de polimorfismos de nucleótido simple (usualmente cientos de miles o millones) en un número grande de individuos (típicamente muchos miles), con el objetivo de proveer un aceptable nivel de información genética a través de todos los cromosomas (el genoma completo) (Corvin 2010).

54 Genetic predisposition to schizophrenia associated with increased use of cannabis Molecular Psychiatry (2014), 1–4 RA Power1 , KJH Verweij3, M Zuhair

55 Genetic predisposition to schizophrenia associated with increased use of cannabis RA Power KJH Verweij Mol Psy 2014 SE MOSTRO QUE AQUELLOS INDIVIDUOS CON CARGA GENETICA PARA EZQUIZOFRENIA TAMBIEN CONSUMIAN MAS CANNABIS Y EN MAS CANTIDAD. ESTO NO SIGNIFICA QUE EL CANNABIS NO AUMENTE EL RIESGO DE PSICOSIS, SINO QUE HAY ALELOS COMPARTIDOS Y CAUSAS BIDIRECIONALES APARENTES

56 Genetic predisposition to schizophrenia associated with increased use of cannabis RA Power KJH Verweij Mol Psy 2014

57 Genetic predisposition to schizophrenia associated with increased use of cannabis Molecular Psychiatry (2014), 1–4 RA Power1,2, KJH Verweij3, M Zuhair Our results show that to some extent the association between cannabis and schizophrenia is due to a shared genetic aetiology across common variants. They suggest that individuals with an increased genetic predisposition to schizophrenia are both more likely to use cannabis and to use it in greater quantities. This is not to say that there is no causal relationship between use of cannabis and risk of schizophrenia, but it does establish that at least part of the association may be due to causal relationship in the opposite direction. Although the variance in cannabis use explained by schizophrenia polygenic risk scores is small, it is in line with other cross-phenotype analyses, largely due to the polygenic risk scores for schizophrenia predicting only ~ 7% of the variation for schizophrenia itself.

58 Genetic predisposition to schizophrenia associated with increased use of cannabis RA Power1,2, KJH Verweij3 Mol Psy 2014 With ongoing debate over the legalization of cannabis and the potential health risks it poses, understanding the association between its use and schizophrenia is a priority. It has previously been suggested that, even assuming an entirely causal relationship, the required reduction in the number of cannabis users to prevent one case of schizophrenia is in the thousands. Our findings here highlight the possibility that this association might be bidirectional in causation, and that the risks of cannabis use could be overestimated. This is an important subtlety to consider when calculating the economic and health impact of cannabis use.

59 Genetic predisposition to schizophrenia associated with increased use of cannabis Mol Psy 2014